6-118553999-A-T

Variant names:

• chr6-118553999-A-T
• rs13192336
• NM_001042475.3:c.1020+11530T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042475.3(CEP85L):​c.1020+11530T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 152,068 control chromosomes in the GnomAD database, including 16,902 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16902 hom., cov: 32)
• Consequence: CEP85L NM_001042475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 3 publications found

Genes affected

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

PLN (HGNC:9080): (phospholamban) The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]

PLN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1P

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 18

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP85L	NM_001042475.3	MANE Select	c.1020+11530T>A		intron	N/A	NP_001035940.1
	PLN	NM_002667.5	MANE Select	c.-97-4826A>T		intron	N/A	NP_002658.1
	CEP85L	NM_001178035.2		c.1029+11530T>A		intron	N/A	NP_001171506.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+11530T>A		intron	N/A	ENSP00000357477.3
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.-97-4826A>T		intron	N/A	ENSP00000350132.5
	CEP85L	ENST00000434604.5	TSL:1	c.1029+11530T>A		intron	N/A	ENSP00000392131.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70579 AN: 151950 Hom.: 16904 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.464 AC: 70597 AN: 152068 Hom.: 16902 Cov.: 32 AF XY: 0.460 AC XY: 34165 AN XY: 74342

African (AFR) AF: 0.392 AC: 16253 AN: 41460

American (AMR) AF: 0.343 AC: 5251 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1548 AN: 3468

East Asian (EAS) AF: 0.302 AC: 1568 AN: 5186

South Asian (SAS) AF: 0.486 AC: 2344 AN: 4824

European-Finnish (FIN) AF: 0.522 AC: 5503 AN: 10542

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.539 AC: 36669 AN: 67978

Other (OTH) AF: 0.435 AC: 920 AN: 2114

Alfa AF: 0.501 Hom.: 2443

Bravo AF: 0.445

Asia WGS AF: 0.375 AC: 1302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.084
DANN	Benign	0.46
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13192336; hg19: chr6-118875162; COSMIC: COSV62645763;